U.S. patent number 6,303,145 [Application Number 09/309,154] was granted by the patent office on 2001-10-16 for (s,r) formoterol methods and compositions.
This patent grant is currently assigned to Sepracor Inc.. Invention is credited to Thomas P. Jerussi, Chris Hugh Senanayake.
United States Patent |
6,303,145 |
Jerussi , et al. |
October 16, 2001 |
(S,R) formoterol methods and compositions
Abstract
A method and composition are disclosed utilizing the pure (S,R)
isomer of formoterol, which is a bronchodilator with reduced
adverse effects. (S,R)-Formoterol may be conveniently and safely
formulated for aerosol administration.
Inventors: |
Jerussi; Thomas P. (Framingham,
MA), Senanayake; Chris Hugh (Shrewsbury, MA) |
Assignee: |
Sepracor Inc. (Marlborough,
MA)
|
Family
ID: |
23196925 |
Appl.
No.: |
09/309,154 |
Filed: |
May 10, 1999 |
Current U.S.
Class: |
424/464; 424/45;
514/553; 514/576; 514/653; 514/826 |
Current CPC
Class: |
A61P
11/00 (20180101); A61K 31/167 (20130101); Y10S
514/826 (20130101) |
Current International
Class: |
A61K
31/167 (20060101); A61K 009/20 (); A61L 009/04 ();
A01N 037/00 (); A01N 033/02 () |
Field of
Search: |
;424/464,478,45
;514/826,653,554,960,964,553,576,630 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2255503 |
|
Nov 1992 |
|
GB |
|
WO92/05147 |
|
Apr 1992 |
|
WO |
|
Other References
Hett, R. et al. "Large-Scale Synthesis of Enantio- and
Diastereomerically Pure (R , R) -Formoterol . . . " Org. Proc. Res.
& Dev. 2, 96-99 (1998). .
Hett, R. et al. "Enantio- and Diastereoselective Synthesis of all
Four Stereoisomers . . . " Tet, Lett. 38, 1125-1128 (1997). .
Testa et al. "Racemates Versus Enantiomers in Drug Development:
Dogmatism . . . " Chirality 2, 129-133 (1990). .
Trofast et al. "Steric Aspects of Agonism and Antagonism at
.beta.-Adrenoceptors; Synthesis . . . " Chirality 3, 443-450
(1991). .
Hett et al. "Conformational Toolbox of Oxazaborolidine Catalysts in
the Enantioselective . . . " Tet. Lett. 39, 1705-1708 (1998). .
Murase et al. "Absolute Configurations of Four Isomers of
3-Formamido-4-hydroxy-. . . " Chem. Pharm. Bull. 26, 1123-29
(1978). .
Ariens "Racemic therapeutics-ethical and regulatory aspects" Eur.
J. Clin. Pharmocol 41, 89-93 (1991). .
Ariens "Stereoselectivity in pharacodynamics and pharmacokinetics"
Schweiz. med. Wochenschr. 120, 131-134 (1990)..
|
Primary Examiner: Hartley; Michael G.
Attorney, Agent or Firm: Heslin Rothenberg Farley &
Mesiti P.C.
Claims
What is claimed is:
1. A method for inducing bronchodilation, relieving or preventing
bronchospasm, reversing or preventing bronchoconstriction and
treating reversible obstructive pulmonary disorders which comprises
administering to a human in need of bronchodilation a
therapeutically effective amount of (S,R)-formoterol, or a
pharmaceutically acceptable salt thereof, said (S,R)-formoterol
containing less than 10% by weight of other isomers of
formoterol.
2. A method according to claim 1 wherein bronchodilation is induced
by administering an amount of (S,R)-formoterol sufficient to effect
bronchodilation but insufficient to cause side effects.
3. The method of claim 1 wherein (S,R) formoterol is administered
by inhalation or oral administration.
4. The method according to claim 3 wherein the amount administered
by inhalation is about 100 .mu.g to about 10 mg per day.
5. A method according to claim 3 wherein said amount is
administered in divided doses from two to four times a day.
6. A pharmaceutical composition in the form of a tablet, capsule or
aerosol formulation which comprises a pharmaceutically acceptable
carrier suitable for a tablet, capsule or aerosol and an amount of
(S,R)-formoterol, or a pharmaceutically acceptable salt thereof,
sufficient to alleviate bronchospasms, said (S,R)-formoterol
containing less than 10% by weight of other isomers of
formoterol.
7. A pharmaceutical composition according to claim 6 adapted for
administration by inhalation wherein the amount of (S,R) formoterol
per unit dose is about 600 .mu.g to about 2.5 mg.
8. A pharmaceutical composition according to claim 6 in the form of
an aerosol formulation, wherein said pharmaceutically acceptable
carrier comprises a propellant.
9. A pharmaceutical composition according to claim 6, wherein said
pharmaceutically acceptable carrier comprises an open matrix of a
polysaccharide or hydrolyzed gelatin.
10. A pharmaceutical composition according to claim 6 for oral
administration.
11. A pharmaceutical composition according to claim 10 in the form
of a syrup.
12. A pharmaceutical composition according to claim 10 in the form
of a tablet or a capsule.
13. An anhydrous pharmaceutical composition according to claim
10.
14. A pharmaceutical composition according to claim 12 in sustained
release form.
15. A pharmaceutical composition for aerosol administration which
comprises a pharmaceutically acceptable carrier suitable for an
aerosol formulation and an amount of (S,R)-formoterol, or a
pharmaceutically acceptable salt thereof, sufficient to provide
from 100 .mu.g to 100 mg of (S,R)-formoterol per unit dose, said
(S,R)-formoterol containing less than 10% by weight of other
isomers of formoterol.
16. A pharmaceutical composition according to claim 15, wherein
said pharmaceutically acceptable carrier comprises a
propellant.
17. A pharmaceutical composition according to claim 15, wherein
said pharmaceutically acceptable carrier comprises an open matrix
of a polysaccharide or hydrolyzed gelatin.
Description
FIELD OF THE INVENTION
The invention relates to pharmaceutical compositions and methods
employing optically pure (S,R) formoterol.
BACKGROUND OF THE INVENTION
Asthma, bronchitis and emphysema are known as Chronic Obstructive
Pulmonary Diseases (COPD). COPD is characterized as generalized
airways obstruction, particularly of small airways, associated with
varying degrees of symptoms of chronic bronchitis, asthma, and
emphysema. The term COPD was introduced because these conditions
often coexist, and it may be difficult in an individual case to
decide which is the major condition producing the obstruction.
Airways obstruction is defined as an increased resistance to
airflow during forced expiration. It may result from narrowing or
obliteration of airways secondary to intrinsic airways disease,
from excessive collapse of airways during a forced expiration
secondary to pulmonary emphysema, from bronchospasm as in asthma,
or may be due to a combination of these factors. Although
obstruction of large airways may occur in all these disorders,
particularly in asthma, patients with severe COPD
characteristically have major abnormalities in their small airways,
namely those less than 2 mm internal diameter, and much of their
airways obstruction is situated in this zone. The airways
obstruction is irreversible except for that which can be ascribed
to asthma.
Asthma is a reversible obstructive pulmonary disorder (ROPD)
characterized by increased responsiveness of the airways. Asthma
can occur secondarily to a variety of stimuli. The underlying
mechanisms are unknown, but inherited or acquired imbalance of
adrenergic and cholinergic control of airways diameter has been
implicated. Persons manifesting such imbalance have hyperactive
bronchi and, even without symptoms, bronchoconstriction may be
present. Overt asthma attacks may occur when such persons-are
subjected to various stresses. Persons whose asthma is precipitated
by allergens (most commonly airborne pollens and molds, house dust,
animal danders) and whose symptoms are IgE-mediated are said to
have allergic or "extrinsic" asthma. They account for about 10 to
20% of adult asthmatics; in another 30 to 50%, symptomatic episodes
seem to be triggered by non-allergenic factors (e.g., infection,
irritants, emotional factors), and these patients are said to have
nonallergic or "intrinsic" asthma.
Formoterol (1), whose chemical name is (+/-)
N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phen
yl]-formamide is a highly potent and .beta..sub.2 -selective
adrenoceptor agonist having a long lasting bronchodilating effect
when inhaled. The structure of formoterol is as shown: ##STR1##
Formoterol's primary use is as a long-acting bronchodilator for the
relief of reversible bronchospasm in patients with obstructive
airway disease such as asthma, bronchitis and emphysema.
The class of .beta..sub.2 agonists, of which formoterol is a
member, cause somewhat similar adverse effects. These adverse
effects include but are not limited to central nervous system
symptoms, such as hand tremors, muscle tremors, nervousness,
dizziness, headache and drowsiness; respiratory side effects, such
as dyspnea, wheezing, drying or irritation of the oropharynx,
coughing, chest pain and chest discomfort; and cardiovascular
effects, such as palpitations, increased heart rate, and
tachycardia. According to Trofast et al. (op. cit.) (R,R)
formoterol is primarily a chronotropic agent in vitro with
inotropic effects showing up at higher concentrations. The
chronotropic effects are reported at concentrations that are higher
than those at which relaxation of tracheal muscle (bronchodilation)
is seen. .beta.-Agonists (e.g. dobutamine) are known in general to
exhibit inotropic activity. In addition, racemic .beta..sub.2
-agonists can cause angina, vertigo, central stimulation and
insomnia, airway hyperreactivity (hypersensitivity), nausea,
diarrhea, dry mouth and vomiting. As with other pharmaceuticals
.beta..sub.2 -agonists sometimes cause systemic adverse effects
such as weakness, fatigue, flushed feeling, sweating, unusual
taste, hoarseness, muscle cramps and backaches.
Furthermore, patients may develop a tolerance to the
bronchodilating effect of the racemic mixture of formoterol. This
is related to desensitization, which is one of the most clinically
significant phenomena involving the beta-adrenergic receptor. The
problem of desensitization is especially significant in the
treatment of diseases involving bronchospasms, such as asthma. The
treatment of asthma usually involves the self-administration,
either orally or by aerosol, of beta-adrenergic agonists such as
the racemic (R,R) (S,S) mixture of formoterol. These agonists
mediate bronchodilation and promote easier breathing. Asthmatic
patients utilizing .beta.-agonists for a prolonged time gradually
increase the self-administered dose in order to get a sufficient
amount of bronchodilation and relief in breathing. As a result of
this increased dosage, the agonist concentration builds to a
sufficient level so as to enter the peripheral circulation where it
acts on the beta receptors of the heart and vasculature to cause
cardiovascular stress and other adverse effects.
Formoterol has two chiral centers (denoted by the asterisks in
formula 1), each of which can exist in two possible configurations.
This gives rise to four combinations: (R,R), (S,S), (R,S) and
(S,R). (R,R) and (S,S) are mirror images of each other and are
therefore enantiomers; (R,S) and (S,R) are similarly an
enantiomeric pair. The mirror images of (R,R) and (S,S) are not,
however, superimposable on (R,S) and (S,R), which are
diastereomers. Formoterol is available commercially only as a
mixture of (R,R) plus (S,S) in a 1:1 ratio, and the generic name
formoterol refers to this racemic mixture. The racemic mixture that
is commercially available for administration is a dihydrate of the
fumarate salt of the formula shown: ##STR2##
The graphic representations of racemic, ambiscalemic and scalemic
or enantiomerically pure compounds used herein are taken from Maehr
J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used
to denote the absolute configuration of a chiral element; wavy
lines indicate disavowal of any stereochemical implication which
the bond it represents could generate; solid and broken bold lines
are geometric descriptors indicating the relative configuration
shown but denoting racemic character; and wedge outlines and dotted
or broken lines denote enantiomerically pure compounds of
indeterminate absolute configuration. Thus, the formula for
formoterol above reflects the racemic nature of the commercial
material, while among the structures below, those having open
wedges are intended to encompass a pure, single configuration which
is one of the two possible at that carbon, and those having solid
wedges are intended to encompass the single, pure isomer having the
absolute stereochemistry shown.
3-Amino-4-hydroxy-.alpha.-[[[2-(4-methoxyphenyl)-
1-methylethyl]amino]methyl]-benzenemethanol (Chem. Abst. Reg. No.
150513-24-9). which is referred to hereinafter as "desformoterol"
(2), has been disclosed as an undesired side product in a synthesis
of formoterol (Spanish Patent ES 2031407). Its structure is shown
below. ##STR3##
Neither its deliberate synthesis nor its pharmacology has been
previously reported. It too exists in four isomeric forms.
All four isomers of formoterol have been synthesized and briefly
examined for relaxing activity on the guinea pig trachea [Murase et
al., Chem. Pharm. Bull. 26, 1123-1129 (1978). It was found that the
(R,R)-isomer is the most potent, while the others are 3-14 times
less potent. More recently, the four isomers have been examined
with respect to their ability to interact in vitro with
.beta.-adrenoceptors in tissues isolated from guinea pig [Trofast
et al., Chirality 3, 443-450 (1991)]. The order of potency was
(R,R)>>(R,S)=(S,R)>(S,S). It was found that the
(R,R)-isomer is 1000-fold more potent than the (S,S)-isomer.
Trofast concluded that "Since the (S,S)-enantiomer is practically
inactive there is from this point of view no reason for its removal
from the racemate in pharmaceutical preparations . . . " In
contradistinction, U.S. Pat. No. 5,795,564 indicates that
administration of the pure (R,R)-isomer provides significant
therapeutic advantages, particularly in avoiding or ameliorating
the side effects seen with racemic formoterol (i.e. 1:1 RR/SS
isomers). No art appears to suggest any advantage to the use of the
pure S,R isomer. In fact, it is one of the two isomers that has for
twenty years been removed from the commercial formoterol
product.
Thus the general conclusion among persons of skill in the art is
that, if there is any advantage to an individual isomer, it resides
in the R,R isomer. However, we have discovered that there are
practical problems associated with the preparation of
pharmaceutical dosage forms of racemic and R,R formoterol. These
problems arise from the extraordinary potency of racemic and R,R
formoterol; it is simply too potent to conveniently formulate for a
metered dose inhaler. Since it is active on. the microgram level,
if even a small amount of active ingredient sticks to the inhaler,
e.g. to the valve components or other interior portions of the
canister, significant overdosing can arise when it is released on a
subsequent activation. There is therefore a need for a medicament
having the advantages of R,R formoterol but less potential for
dose-to-dose variability in formulations.
SUMMARY OF THE INVENTION
The present invention relates to compositions and methods employing
the S,R isomer of Formoterol (3). These compositions may also
include S,R-desformoterol (4), which has a similar pharmacological
profile: ##STR4##
It has now been discovered that the (S,R) isomer of formoterol is
an effective bronchodilator that may be safely formulated for
reproducible aerosol administration. It possesses similar
.beta..sub.2 selectivity to that of the corresponding R,R isomer
and therefore avoids certain adverse effects associated with the
racemic form.
In one aspect the invention relates to methods of inducing
bronchodilation or preventing bronchoconstriction with (S,R)
formoterol comprising administering to an individual a
therapeutically effective amount of (S,R)-formoterol, which is a
quantity of (S,R) formoterol sufficient to induce bronchodilation
or prevent bronchoconstriction. The (S,R) formoterol may be
administered orally or by subcutaneous injection, intravenous
infusion, inhalation, or transdermal delivery. Inhalation is
preferred. Preferably the (S,R)-formoterol contains less than 10%
by weight of other isomers of formoterol, and in particular, less
than 1% by weight of the R,R enantiomer. More preferably the
(S,R)-formoterol contains less than 5% by weight of other isomers
of formoterol; most preferably the (S,R)-formoterol contains less
than 2% by weight of other isomers of formoterol. The amount
administered by inhalation is about 100 .mu.g to about 10 mg per
day, in single or divided doses.
The present invention also includes pharmaceutical compositions
containing (S,R) formoterol of the optical purity described above.
The pharmaceutical compositions may be in the form of a tablet,
capsule or aerosol formulation, and they comprise a
pharmaceutically acceptable carrier suitable for a tablet, capsule
or aerosol and an amount of (S,R)-formoterol, or a pharmaceutically
acceptable salt thereof, sufficient to alleviate bronchospasms.
Compositions for administration by inhalation contain about 600
.mu.g to about 2.5 mg of (S,R) formoterol and the pharmaceutically
acceptable carrier may include a propellant. Compositions for oral
administration include syrups, tablets and capsules. Anhydrous
compositions are preferred.
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses a method of eliciting a
bronchodilator effect while avoiding the concomitant liability of
adverse effects or development of tolerance, which comprises
administering to a human in need of bronchodilation an amount of
(S,R) formoterol or (S,R) desformoterol sufficient to alleviate
bronchospasms, but insufficient to cause said adverse effects,
development of tolerance or hypersensitivity.
The present invention provides a method or use for the treatment of
ROPD, in particular for effecting bronchodilatation, as a means of
alleviating airways obstruction, in particular acute airways
obstruction, e.g. asthma attack, occurring in such disease. The
invention thus provides symptomatic therapy for such disease. The
present invention is applicable in the therapy of obstructive
airways disease and, in general, any such disease for which
.beta..sub.2 agonists are commonly employed in therapy.
The present invention provides means to avoid, ameliorate or
restrict deleterious side effects observed in patients consequent
to conventional clinical usage of .beta..sub.2 agonists as racemic
mixtures, for example "anomalous", "rebound" or "paradoxical"
bronchospasm and, especially, increase in airway obstruction,
exacerbation of late asthmatic response or non-specific bronchial
reactivity or arterial hypoxemia.
A mixture of formoterol isomers can be prepared according to U.S.
Pat. No. 3,994,974. The diastereomers may be separated as described
by Murase et al. [Chem. Pharm. Bull. 25, 1368-13 (1977)]. The
individual isomers of formoterol may be obtained as described by
Trofast et al. (op. cit.) by stereocontrolled synthesis from
optically active starting material or by resolution of a mixture of
enantiomers (i.e., the racemic mixture) using conventional means,
such as an optically active resolving acid.
An enantioselective synthesis is described below:
To 800 mL of methanol were added 328 g of 4-methoxyphenylacetone (2
mol) and 214 g of N-benzylamine (2 mol). The imine formation was
exothermic and the solution warmed to 45.degree. C. After reaction
was complete. the solution was hydrogenated at 50 psi for 6-8 hours
in the presence of 3.3 g of 5% platinum on carbon catalyst. When
the hydrogen uptake had stopped, the reaction was filtered through
diatomaceous earth, and the filter cake was washed with 200 mL of
methanol. The combined filtrates were placed in a 6-liter flask and
diluted with 4.2 liters of methanol. (S)-L-Mandelic acid (304 g, 2
mol) was added and the mixture heated with stirring to reflux to
obtain a clear solution. The solution was cooled to room
temperature, stirred at room temperature for two hours and the
mandelic acid salt filtered off. The recrystallization was repeated
three times to obtain 60-70 g of
4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethaneamine
L-mandelic acid salt having an isomeric purity greater than 99.8%
and a melting point of 164.degree. C.
A 5-liter flask was charged with 300 g (1.1 mol) of
4-benzyloxy-3-nitroacetophenone and 3 liters of acetonitrile. The
mixture was heated to 50.degree. C. to form a clear solution, and
180 g of bromine (1.6 mol) was added in one portion. The reaction
was stirred at 50.degree. for 15-25 minutes, during which time the
deep red color changed to pale orange and TLC (ethyl acetate/hexane
3:7) showed no remaining starting material. Without heating, 200 to
300 mL of acetonitrile, along with the byproduct hydrogen bromide,
were distilled from the reaction under vacuum. During the course of
the distillation, the temperature dropped to about 15.degree. and
the product precipitated as a yellow solid. The reaction was
stirred at 0-5.degree. for two hours and the product filtered off
and washed with acetonitrile. The resulting 2-bromo 4'-benzyloxy-3'
nitroacetophenone was dried in vacuum to yield 242 g (63%) of
off-white solid having a melting point of 136.degree. C.
In an improved procedure, bromine was replaced by pyridinium
tribromide and the bromination was carried out at room temperature.
The 2-bromo-4'-benzyloxy-3'-nitroacetophenone product was isolated
by addition of water.
A 2-liter flask is charged with 2.5 g (17 mmol) of
(1S,2R)-aminoindanol in 50 mL of THF under argon. While cooling to
maintain a temperature below 25.degree. C., 3.4 mL (34 mmol) of a
10 mol solution of borane methyl sulfide is added over a period of
5 minutes and the reaction stirred for ten minutes at 25.degree. C.
to complete formation of the catalyst. To this catalyst solution
the ketone and reducing agent are added simultaneously.
From'separate reservoirs are added (1) a solution of 120 g of
2-bromo-4'-benzyloxy-3'-nitroacetophenone (0.34 mol) in 950 mL of
THF and (2) 24 mL of 10 M borane-methyl sulfide. Addition is over a
period of 3 hours at 25.degree. C. The reaction is cooled on an ice
bath and 100 mL of methanol is added over a period of 15 minutes.
The reaction mixture is concentrated under vacuum to a volume of
about 200 mL, and 650 mL of toluene is added to dissolve the
residue. The solution is washed with 0.2 M sulfuric acid and then
water. If desired the aminoindanol may be recovered from the
aqueous acidic phase. The organic phase was dried over sodium
sulfate, filtered and concentrated to a weight of 240-260 g. A
total of 100 mL of heptane is added to the mixture with stirring at
50-60.degree., then cooled to 15-20.degree. and filtered. The wet
filter cake may be used in the next step without drying or the
solid may be dried under vacuum to give
(S)-.alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzemethanol as
an off white solid, melting point 68.degree. C.
An alternative reduction employs borane-diethylaniline: A 50-liter
flask is charged with 70 g (0.5 mol) of (1S,2R)-aminoindanol in 10
L of THF under argon. While cooling to maintain a temperature below
25.degree. C., 1.9 L (10 mol) of a 5.6 M solution of borane
diethylaniline is added over a period of 20 minutes and the
reaction stirred for 30 minutes at 15-25.degree. C. to complete
formation of the catalyst. The solution is cooled to 0-5.degree. C.
and a carefully dried solution of 3.5 kg of
2-bromo-4'-benzyloxy-3'-nitroacetophenone (10 mol) in 32 L of THF
is added over a period of at least 2 hours at 0-5.degree. C. After
addition is complete, 3.9 L of acetone is added over a period of 20
minutes, keeping the temperature at 5-15.degree. C. The reaction
mixture is concentrated under vacuum to a volume of about 10.5 L,
and 24 L of toluene is added to dissolve the residue. The solution
is washed with 1.0 M sulfuric acid and then brine. The organic
phase is concentrated to a volume of 10.5 L twice with toluene to
reduce the water to <0.02% by Karl Fischer titration. The
mixture is cooled with stirring to 24.degree. C. and seeded, then
cooled very slowly to 20.degree. and 7.2 L of heptane is added to
the slurry with stirring. The mix is filtered and rinsed with
heptane. The solid is dried at 25.degree. C. to give
(S)-.alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzemethanol.
A solution of 100 g (0.28 mol) of
(S)-.alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzemethanol in
200 mL of THF and 200 nL of toluene is hydrogenated in a Parr
hydrogenator in the presence of 1 g of platinum oxide catalyst at
45-50 psi for 7-13 hours until hydrogen uptake ceases. The reaction
mixture is filtered through a bed of diatomaceous earth and a
solution of 21.5 g (0.48 mol) of formic acid and 33 g (0.32 mol) of
acetic anhydride, which have been pre-mixed, is added to the
filtrate, which is maintained at 10-15.degree. C. by external
cooling. The solution is stirred for 20 minutes at 10-25.degree. C.
and then concentrated to about 300 mL at 30.degree. C. One hundred
milliliters of toluene is added and the reaction is stirred at
15.degree. C. for 15 minutes. The resulting slurry is filtered to
provide
(S)--N-[5-(2-bromo-1-hydroxyethyl)-2-(phenylmethoxy)phenyl]formamide
having a melting point 130.degree. C., isomeric purity 99-99.5%.
The product is also sometimes referred to as
2-bromo-(4'-benzyloxy-3'-formamidophenyl)ethanol.
An alternative reduction using 6 g of 10% platinum on carbon and 0.
12-0.5 g of dimethyl sulfide, with no toluene, gives cleaner
product when BH.sub.3 THF is used as the reducing agent in the
previous step. The use of 30 g of formic acid to prepare the mixed
anhydride may improve yields.
A 2-liter flask was charged with 75 g of
(S)--N-[5-(2-bromo-1-hydroxyethyl)-2-(phenylmethoxy)phenyl]-formamide
(0.21 mol), 92 g of
(R)-4methoxy-.alpha.-methyl-N-(phenylmethyl)benzene-ethaneamine
L-mandelic acid salt (0.23 mol), 75 g of milled potassium carbonate
(0.6 mol, 325 mesh), 425 mL of THF and 425 mL of methanol. The
mixture was stirred under argon at 25.degree. until <0.5% of the
formamide starting material remained. The mixture was concentrated
to approximately 550 mL, by distillation. To the residue was added
225 mL of toluene and the mixture was distilled again to 500 mL.
This was repeated twice and the final volume reduced to about 225
mL. Five hundred milliliters of water was added. The slurry was
stirred 10 minutes, the phases were separated and the slurry and
separation processes repeated. The toluene solution was disitiled
under vacuum at 120.degree. C. to completely remove the toluene.
The residue was stirred at 120.degree. C. until less than 2.5% of
the N-benzyl-2-amino-(4-methoxyphenyl)propane remained (about 8
hours). The solution was cooled to 83.degree. C. and 100 mL of
carbon tetrachloride was added. The carbon tetrachloride solution
was poured onto a silica gel column and flash chromatographed with
cyclohexane/dichloromethane/MTBE (2:1:1) to yield 24 g of dibenzyl
protected formnoterol.
The S,R dibenzyl protected formnoterol (13.84 g) was dissolved in
28 mL of ethanol and transferred to a Parr hydrogenator and
hydrogenated at 45-50 psi in the presence of 1.9 g of 10% palladium
on carbon until hydrogen uptake was complete (3-4 hours) and less
than 0.5% of the monobenzyl formoterol remained. The mixture was
filtered through a pad of diatomaceous earth and washed with 25 mL
of ethanol. The ethanol was removed in vacuo and 78 mL of
2-propeanol was added. The mixture was heated to reflux until a
clear solution was formed. As soon as the clear solution formed,
heating was discontinued and the mixture was cooled to 23.degree.,
at which temperature it was held for 2 days. The product was
collected by filtration, washed with 2-propanol and dried under
vacuum to provide 3.69 g of (S,R) formoterol free base.
The magnitude of a prophylactic or therapeutic dose of (S,R)
formoterol in the acute or chronic management of disease will vary
with the severity of the condition to be treated, and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight, and response of the
individual patient. In general, the total daily dose ranges when
administered by inhalation, for the conditions described herein, is
from about 100 .mu.g to about 10 mg, in single or divided doses.
Preferably, a daily dose range should be between about 600 .mu.g to
about 2.5 mg, in single or divided doses, while most preferably, a
daily dose range should be between about 1.2 mg to about 2.5 mg, in
from two to four divided doses. In managing the patient, the
therapy should be initiated at a lower dose, perhaps about 300
.mu.g to about 1.2 mg, and increased up to about 2.times.1.2 mg or
higher depending on the patient's global response. When
administered orally, preferably as a tablet, the preferred dose
range is from 10 to 100 mg per day. It is further recommended that
children, and patients over 65 years, and those with impaired
renal, or hepatic function, initially receive low doses, and that
they be titrated based on individual responses) and blood level(s).
It may be necessary to use dosages outside these ranges in some
cases as will be apparent to those skilled in the art. Further, it
is noted that the clinician or treating physician would know how
and when to interrupt, adjust, or terminate therapy in conjunction
with individual patient response.
The terms "an amount sufficient to alleviate bronchospasms but
insufficient to cause said adverse effects" are encompassed by the
above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing
the patient with an effective dosage of (S,R) formoterol. For
example, oral, rectal, parenteral (subcutaneous, intramuscular,
intravenous), aerosol, transdermal, and like forms of
administration may be employed. Dosage forms include tablets,
troches, dispersions, suspensions, solutions, capsules, patches,
and the like.
The pharmaceutical compositions of the present invention comprise
(S,R) formoterol and/or (S,R) desformoterol as the active
ingredient, or a pharmaceutically acceptable salt thereof, and may
also contain a pharmaceutically acceptable carrier, and optionally,
other therapeutic ingredients. The term "pharmaceutically
acceptable salts" or "a pharmaceutically acceptable salt thereof"
refer to salts prepared from pharmaceutically acceptable nontoxic
acids including inorganic acids and organic acids. Suitable
pharmaceutically acceptable acid addition salts for the compound of
the present invention include acetic, benzenesulfonic (besylate),
benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic, and the like. The fumaric and tartaric acid
salts are particularly preferred.
The compositions of the present invention include compositions such
as suspensions, solutions, elixirs; aerosols and solid dosage
forms, with carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents, and the like. The compositions include
compositions suitable for oral, rectal, parenteral (including
subcutaneous, transdermal, intramuscular, and intravenous) and
inhalation, although the most suitable route in any given case will
depend on the condition being treated and the nature and severity
of that condition. The most preferred routes of the present
invention are: (1) oral by either tablets or capsules, (2)
inhalation and (3) transdermal by patch. They may be conveniently
presented in unit dosage form and prepared by any of the methods
well-known in the art of pharmacy.
In addition to the common dosage forms set out above, the compounds
of the present invention may also be administered by controlled
release means and/or delivery devices such as those described in
U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and
4,008,719, the disclosures of which are hereby incorporated by
reference. Because they reduce peak plasma concentrations,
controlled release dosage forms are particularly useful for oral
administration in that they provide a therapeutic plasma
concentration of S,R-desformoterol or S,R-formoterol while avoiding
the side effects associated with peak plasma concentrations.
EXAMPLE 1 Formula for Inhalation Quantity contained in Each Formula
Metered Dose Dispenser (S,R,)-formoterol 180 mg
trichloromonofluoromethane 15.16 g dichlorodifluoromethane 15.16 g
sorbitan trioleate 1.05 g
The metered dose dispenser contains micronized (S,R)-formoterol in
suspension. Each actuation delivers 0.6 mg of (S,R)-formoterol from
the mouthpiece. Each canister provides about 300 inhalations.
EXAMPLE 2 Compressed tablets Per tablet Per 10,000 tablets
(S,R)-Formoterol 10 mg 100 g Starch 60 mg 600 g Talc 12 mg 120 g
Acacia 12 mg 120 g Stearic Acid 1 mg 10 g
Tablets may be prepared using conventional wet granulation
techniques, such that each dosage unit contains 0.1 mg to 10 mg of
formoterol. The acacia and an equal weight of starch is blended to
form a paste which is used to granulate the formoterol. The mixture
is dried and placed through a mesh screen. The remainder of the
material is added and mixed thoroughly. The resulting mixture is
compressed into tablets using a 9/32-inch (7 mm) punch.
Sustained release tablets may be prepared by methods well known in
the pharmaceutical art. (See Remington: The Science and Practice of
Pharmacy 19th Edition 1995, Chapter 94 and U.S. Pat. No. 5,674,895
the disclosures of which are incorporated herein by reference.) An
exemplary sustained release formulation is shown below.
EXAMPLE 3 Sustained release tablets Per tablet Per 10,000 tablets
(S,R)-Formoterol 10 mg 100 g HPMC 2208 USP l00 mg l000 g Carnauba
wax 20 mg 200 g HPMC 2910 USP l0 mg l00 g Talc 5 mg 50 g Magnesium
stearate 1 mg 10 g Stearic Acid 4 mg 40 g
The first three ingredients are placed in a granulator and mixed
for 15 minutes. The hydroxypropylmethylcellulose is dissolved in
water by warming and then cooled and sprayed onto the fluidized
mixture. The granules are dried to 5% moisture. The last three
ingredients are added sequentially with mixing. The mixture is
compressed into tablets.
Another formulation that lends itself to aerosol administration of
S,R-formoterol is a solid state open matrix network that allows one
to quickly generate a precisely controlled volume of an aqueous
solution suitable for aerosol administration. Preferably the solid
state matrix disintegrates (dissolves or disperses) within 10
seconds or less. Such dosage forms are described in copending
application Ser. No. 09/168,216, filed Oct. 7, 1998, the pertinent
disclosure of which is incorporated herein by reference. The
carrier material used may be any water-soluble or water-dispersible
material that is pharmacologically acceptable or inert to the
formoterol and that is capable of forming a rapidly disintegratable
open matrix network. Use of a water-soluble material as the carrier
results in the most rapid disintegration of the matrix when the
product is placed in an aqueous medium. A particularly advantageous
carrier may be formed from a protein such as gelatin, particularly
partially hydrolyzed gelatin. The hydrolyzed gelatin is preferably
used at concentrations of about 1 to 6% weight/volume based on the
volume of the initial solution, prior to lyophilization. Other
carrier materials include polysaccharides such as hydrolyzed
dextran, dextrin and alginates (e.g. sodium alginate) or mixtures
of above mentioned carriers with each other or with other carrier
materials such as polyvinyl alcohol, polyvinylpyrrolidine or
acacia. The solid state matrices may incorporate ingredients in
addition to the medicament, for example coloring agents, flavoring
agents, preservatives (e.g. bacteriostatic agents), and the
like.
The solid state matrices are prepared by subliming (lyophilizing)
solvent (usually water) from a composition comprising the
formoterol and a solution of the carrier material in a solvent, the
composition being in the solid state in a mold, which can be a
reservoir for a nebulizer. Although the solvent is primarily water,
it may contain a co-solvent such as t-butanol when necessary to
improve the solubility of the medicament. The composition may also
contain a surfactant e.g. Tween 90 [polyoxyethylene (20)
sorbitan-mono-oleate] to aid in the dispersion of the
medicament.
The mold may be in the form of a tray having a series of
cylindrical or other shape depressions in it, each of a size
corresponding to the desired size of the solid state matrix.
Alternatively, the size of the depression may be larger than the
desired size of the article and, after the contents have been
freeze dried, the product can be cut into the desired size (for
example thin wafers). The following examples illustrate these
matrix formulations:
EXAMPLE 4
A hydrolyzed gelatin solution is prepared by dissolving 30 g of
gelatin in 1 L of water and heating at 121.degree. C. at 1.03 bar
for one hour. The solution is allowed to cool to room temperature.
One gram of S,R-formoterol or an S,R-formoterol salt is dissolved
in the solution. A mold in the form of an aluminum film containing
75 cylindrical depressions (each depression being about 0.5 cm
diameter and 1 cm deep) is cooled to about -192.degree. C. in
liquid nitrogen contained in a stainless steel tray. One half
milliliter of the mixture is introduced into each depression and
frozen. The mold is placed in a vacuum chamber at room temperature
and a vacuum of 0.3 mm Hg is applied for 12 hours. The freeze dried
matrices, each containing 0.5 mg of formoterol (about 10 to 20 unit
doses), are covered with a pealable aluminum seal.
EXAMPLE 5
Twenty grams of acacia is placed in a dry 1 L flask and about 10 mL
of absolute alcohol is added. The flask is shaken to wet the acacia
powder, and 500 mL of distilled water is introduced and shaken to
yield a homogeneous solution. Thirty grams of polyvinylpyrrolidine
and 1 g of S,R-fornoterol are dispersed into the solution with the
aid of ultrasonic vibration. The final volume is adjusted to 1L
with distilled water and 1 mL of the composition is added to each
container (for multiple doses) or 20 to 50 .mu.L is added to each
container (for a unit dose). The lyophilization is carried out as
described above. The container is then sealed with a pealable
seal.
The matrices prepared according to example 4 may be provided to the
user as a component of a kit. The other component of the kit is a
container containing the appropriate amount of buffered saline, or
other suitable aqueous vehicle, sufficient to dissolve a single
matrix (wafer) and provide a sterile, homogenous solution of
precisely controlled concentration. Thus, for example, a wafer may
contain 2-5 mg of S,R-formoterol, which is the range for one unit
dose for inhalation. In that case, the second container may contain
5 mL of saline. The second container containing the saline may be a
sealed nebulizer reservoir. In use, the wafer would be transferred
from its sealed blister pack into a nebulizer reservoir and
combined with the saline components. The wafer dissolves within
seconds and provides the solution for a single inhalation
session.
Alternatively, matrices may be prepared in accordance with example
5, wherein the container in which the solution is lyophilized is a
reservoir for use in a nebulizer. The kit would then comprise the
matrix in a sealed nebulizer reservoir as the first component and a
container containing the appropriate amount of buffered saline, or
other suitable aqueous vehicle, sufficient to dissolve the matrix
as the other container.
A study was carried out to determine the stability of a formulation
comprised of S,R-formoterol and lactose, in the presence and
absence of 5% water. A series of amber 20 mL, crimp-topped vials
were prepared to contain S,R-formoterol and lactose. The contents
of the vials were (1) dry S,R-formoterol; (2) 20% dry
S,R-formoterol and 80% lactose; and (3) 19% S,R-formoterol, 76%
lactose and 5% H.sub.2 O. The vials were placed in a 60.degree. C.
or a 40.degree. C. oven and then assayed via high-performance
liquid chromatography (HPLC) at 256 nanometers. The only
significant degradation seen was in the vial containing 5% H.sub.2
O. This sample represents the worst case scenario for a
drug/excipient interaction as stated in Drug Stability (Carstensen
et al., pp.379-380). These data indicate that under accelerated
conditions for excipient interaction studies, the combination of
.alpha.-lactose monohydrate and water adversely affects the
stability of S,R-formoterol, while a solid dose
S,R-formoterol/lactose composition in the absence of 5% moisture
does not show this high degree of degradation. These results are
presented in Table 1, below.
TABLE 1 Potency (%); Potency (%); 60.degree./75% RH 40.degree.
C./75% RH Sample 1 week 1 month 1 month 3 months (S,R) formoterol
(Fm) 99.1 98.9 99.8 98.5 (S,R) Fm/lactose 101.0 99.0 99.4 98.8
(S,R) Fm/water 99.1 98.9 98.4 98.3 (S,R) Fm/lactose/water 94.7 3.2
98.9 95.7
The following tests were used to characterize the pharmacology of
(S,R)-formoterol and (S,R)-desformoterol.
First Series
(R,RIS,S)-, (R,R)-, (S,R)-, (R,S)-, and (S,S)-formoterol were
evaluated for their affinities to .beta..sub.1 and .beta..sub.2
-receptors, their capacity to stimulate cAMP production (intrinsic
activity), and their propensity to cause densensitization.
Formoterol and its enantiomers were evaluated in radiolabeled
binding assays with [.sup.125 I]-iodopindolol (45-85 pM) to
determine their respective affinities for recombinant human
.beta..sub.1 - and .beta..sub.2 -adrenergic receptors expressed in
Spodoptera frugiperda (Sf9) cells. Each compound was tested at
various concentrations (10.sup.-9 -10.sup.-3 M) in each of the two
receptor membrane preparations. Dissociation constants (K.sub.ds)
were then determined and tabulated in Table 2.
TABLE 2 .beta..sub.2 Intrinsic K.sub.d (nM) Selectivity Activity
Formoterol .beta..sub.1 .beta..sub.2 (.beta..sub.1 /.beta..sub.2)
(cAMP) (R,R/S,S) 192 5.2 36.9 0.94 (R,R) 113 2.9 39.0 1.02 (S,R)
2,500 75 33.0 0.91 (R,S) 133 103 1.3 0.65 (S,S) 6,800 3,100 2.2
0.18 Isoproterenol 24 37 0.6 1.00
(R,R)-Formoterol had the greatest potency and the most selectivity
(nearly 40-fold) at the .beta..sub.2 -adrenergic receptor.
The assessment of intrinsic activity was evaluated in BEAS-2B cells
grown to confluence. Cells were washed and stimulated for 0-30
minutes with PBS containing ascorbate, a phosphodiesterase
inhibitor, and either vehicle or 100-times the K.sub.d
concentration of formoterol or its isomers. Samples were assayed
for cAMP by radioirmmunoassay. (R,R/S,S)-, (R,R)-, and
(S,R)-formoterol displayed high intrinsic activities relative to
isoproterenol (intrinsic activity set to 1.0). Whereas (R,S)- and
(S,S)-formoterol showed moderate and low intrinsic activities,
respectively.
Beta.sub.2 -receptor responsiveness was evaluated in BEAS-2B cells
pretreated for 0-48 hours with formoterol or its isomers. The
pretreated cells were then stimulated with 10 .mu.M isoproterenol
and cAMP accumulation was measured. Pretreatment with each of the
compounds at K.sub.d concentrations produced a rapid loss of
isoproterenol-stimulated cAMP production (t.sub.1/2 <1 hour for
each compound). The (R,S)- and (S,S)-enantiomers had significant
but smaller effects. Qualitatively similar, but slightly more rapid
effects were observed with pretreatment with concentrations
100-times the K.sub.d.
Beta.sub.2 -adrenergic receptor down-regulation was evaluated in
BEAS-2B cells treated for 0-38 hours with formoterol and its
isomers at either the K.sub.d or 100-times the K.sub.d
concentration. Receptor density was estimated by one-point analysis
using [.sup.125 I]iodopindolol. (R,R/S,S)-, (R,R)-, and
(S,R)-formoterol at the K.sub.d elicited a rapid down-regulation
(t.sub.1/2.about.4 hours). (S,S)-Formoterol, on the other hand,
displayed a time-course significantly slower (t.sub.1/2.about.6
hours) than those of the other compounds. Down-regulation at higher
concentrations (100-times the K.sub.d) occurred at a slightly
faster rate, and the relatively greater effects of
(R,R/S,S)-(R,R)-, and (S,R)-formoterol on receptor loss still
prevailed over those observed for the (R,S)- and
(S,S)-enantiomers.
Second Series
(R,S)- and (S,R)-desformoterol were screened, in duplicate at three
concentrations (10.sup.-9, 10.sup.-7, 10.sup.-5 M), for binding to
human .beta..sub.1 and .beta..sub.2 -adrenergic receptors.
Compounds that inhibited specific binding .gtoreq.50% were then
tested further at ten concentrations in duplicate in order to
obtain full competition curves. Reference compounds were
simultaneously tested at eight concentrations. IC.sub.50 values
(concentration required to inhibit 50% of specific binding) were
determined by nonlinear regression analysis and tabulated in Table
3.
TABLE 3 IC.sub.50 (nM) Compound .beta..sub.1 .beta..sub.2
(R,S)-Desformoterol 1,790 3,140 (S,R)-Desformoterol -- 1,830
Atenolol 1,430 -- ICI 118551 -- 2.4
The binding of (R,S)-desformoterol was comparable to that of
atenolol at the .beta..sub.1 -site, and an IC.sub.50 was not
determined for (S,R)-desformoterol because only 22% inhibition was
attained at 10.sup.-5 M.
The comparative results are shown in Table 4:
TABLE 4 .beta..sub.2 Intrinsic Selectivity Activity .beta..sub.1
.beta..sub.2 (.beta..sub.1 /.beta..sub.2) (cAMP) (R)-Albuterol (mM)
Second series 9.9 4.1 2.4 First series 1.540 0.236 6.5 0.44
Desformoterol (nM) Second series (human) (R,R/S,S) 5,142 81.3 63
(R,R) 3,180 35.6 89 (S,S) 64,710 >10,000 -- (R,S) 1,790 3,140
0.6 (S,R) -- 1,830 -- Formoterol (nM) Second series (R,R/S,S) 1,500
900 1.6 (R,R) 710 150 4.7 (S,S) 7,100 2,200 3.2 (human) (R,R/S,S)
344 4.9 70 (R,R) 199 2.3 86 Formoterol (nM) First series (R,R/S,S)
192 5.2 37 0.94 (R,R) 113 2.9 39 1.02 (S,S) 6,800 3,100 2.2 0.18
(R,S) 133 103 1.3 0.65 (S,R) 2,500 75 33 0.91
* * * * *